DESCRIPTION: This proposal concerns the relationship between hepatitis C virus (HCV) and cytotoxic T lymphocytes (CTL) during the evolution of chronic persistent HCV infection in humans. Although it is known that a polyclonal CTL response to HCV proteins is elicited in this disease, there is no understanding of why these cells fail to clear the virus, as would normally be expected from such effector cells. Several distinct hypotheses are presented for investigation of the molecular and cellular basis for this phenomenon, and will be addressed in four specific aims. Specific aim 1 will determine whether the strength of the CTL response is a major determinant of the capacity to clear HCV infection. Specific aim 2 will address whether mutations in viral CTL epitopes are involved in the initiation and maintenance of persistent infection. The third specific aim is to determine whether HCV proteins, in particular, the E1 glycoprotein can inhibit Class I antigen presentation and also whether viral infection can render hepatocytes resistant to CTL-mediated killing. The fourth and final aim is to establish whether hepatocytes can anergize or delete CTL responses as a result of suboptimal antigen presentation.